Malformations of cortical development

Gene: TMEM161B

Green List (high evidence)

Comment on phenotypes: TMEM161B is not yet associated with a phenotype in OMIM (accessed 3rd Nov 2026).

Created: 3 Nov 2026, 12:09 p.m. | Last Modified: 3 Nov 2026, 12:10 p.m.

Panel Version: 8.16

Comment on list classification: As reviewed by Alexandra Njegic, there are more than 3 unrelated probands reported in literature with biallelic TMEM161B variants and polymicrogyria. The TMEM161B null mouse model is also supportive of this association. Hence, this gene can be promoted to Green on Malformations of cortical development.

Created: 3 Nov 2026, 12:08 p.m. | Last Modified: 3 Nov 2026, 12:11 p.m.

Panel Version: 8.16

PMID: 36669109 Wang et al., 2023
Study of a polymicrogyria (PMG) cohort identified four families with affected children showing nearly identical neocortical PMG. Brain imaging in each showed dramatic symmetrical PMG, without a clear lobar or regional predominance. WES revealed homozygous variants in TMEM161B: c.949C>T; p.W317R in Families I & II, and c.254T>G; p.L85R in Families III and IV. All 4 families were from Egypt and had consanguinity reported. Parents unaffected. Mild microcephaly reported at birth (HC -0.5 to -1.5 SD), progressing to severe at last examination in all 4 probands (head circumference -3 to -4.5 SD). Intellectual disability was moderate to profound.

PMID: 37486637 Akula et al., 2023
Proband BFP903-905 - comp het for TMEM161B variants: c.362C>T p.Thr121Ile & c.580G>A p.Glu194Lys. Diffuse PMG, bilateral (neuropathologic examination) of BFP906, 903-905 similar clinical syndrome with no imaging. Head circumference unknown. Same variants as third family in PMID: 36669111 (same research group) - likely the same proband.

Created: 3 Nov 2026, 12:07 p.m. | Last Modified: 3 Nov 2026, 2:22 p.m.

Panel Version: 8.16

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
polymicrogyria, MONDO:0000087; microcephaly, MONDO:0001149

Publications

• 36669109
• 36669111
• 38593811
• 37486637

I don't know

PMID: 36669111 describes 3 families with either homozygous or compound heterozygous for variants in TMEM161B. Variants described in the article are missense or splice site (splice site was shown in PMID 38593811 to result in skipping of exon 8 which resulted in an removal of the 'most highly conserved portion of the protein'). Article also generated and describe TMEM161B null mice which broadly phenocopy the clinical indications described in the 3 families (null mice show holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes) ; there is a suggestion that TMEM161B interacts with SHH but within the CNS. Data is supported by gnomAD - within MANE select there are no homozygous LOF variants recorded; only LOF variant present in the homozygous state occurs downstream of the MANE select (in TMEM161-213).

Created: 3 Sep 2026, 10:26 a.m. | Last Modified: 3 Sep 2026, 10:26 a.m.

Panel Version: 8.11

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Polymicrogyria

Publications

• 36669111
• 38593811
• 37486637